tbuckley/cabot-search huggingface dataset:
Dissecting the Mechanisms Underlying the Cytokine Release Syndrome (CRS) Mediated by T-Cell Bispecific Antibodies
Authors: Gabrielle Leclercq-Cohen, Nathalie Steinhoff, Llucia Albertí Servera, Sina Nassiri, Sabrina Danilin, Emily Piccione, Emilio Yángüez, Tamara Hüsser, Sylvia Herter, Stephan Schmeing, Petra Gerber, Petra Schwalie, Johannes Sam, Stefanie Briner, Sylvia Jenni, Roberta Bianchi, Marlene Biehl, Floriana Cremasco, Katerina Apostolopoulou, Hélène Haegel, Christian Klein, Pablo Umaña, Marina Bacac
Journal: Clinical Cancer Research (2023)

Target-dependent TCB activity can result in the strong and systemic release of cytokines that may develop into cytokine release syndrome (CRS), highlighting the need to understand and prevent this complex clinical syndrome.We explored the cellular and molecular players involved in TCB-mediated cytokine release by single-cell RNA-sequencing of whole blood treated with CD20-TCB together with bulk RNA-sequencing of endothelial cells exposed to TCB-induced cytokine release. We used the in vitro whole blood assay and an in vivo DLBCL model in immunocompetent humanized mice to assess the effects of dexamethasone, anti-TNFα, anti-IL6R, anti-IL1R, and inflammasome inhibition, on TCB-mediated cytokine release and antitumor activity.Activated T cells release TNFα, IFNγ, IL2, IL8, and MIP-1β, which rapidly activate monocytes, neutrophils, DCs, and NKs along with surrounding T cells to amplify the cascade further, leading to TNFα, IL8, IL6, IL1β, MCP-1, MIP-1α, MIP-1β, and IP-10 release. Endothelial cells contribute to IL6 and IL1β release and at the same time release several chemokines (MCP-1, IP-10, MIP-1α, and MIP-1β). Dexamethasone and TNFα blockade efficiently reduced CD20-TCB-mediated cytokine release whereas IL6R blockade, inflammasome inhibition, and IL1R blockade induced a less pronounced effect. Dexamethasone, IL6R blockade, IL1R blockade, and the inflammasome inhibitor did not interfere with CD20-TCB activity, in contrast to TNFα blockade, which partially inhibited antitumor activity.Our work sheds new light on the cellular and molecular players involved in cytokine release driven by TCBs and provides a rationale for the prevention of CRS in patients treated with TCBs. See related commentary by Luri-Rey et al., p. 4320.
PRMT5 reduces immunotherapy efficacy in triple-negative breast cancer by methylating KEAP1 and inhibiting ferroptosis
Authors: Zhe Wang, Ruolei Li, Niuniu Hou, Juliang Zhang, Ting Wang, Pengyu Fan, Cheng Ji, Bo Zhang, Liuyin Liu, Yaping Wang, Jing Kong, Qing Yao, Jie Duan, Ge Zhao, Rui Ling, Jian Zhang
Journal: Journal for ImmunoTherapy of Cancer (2023)

As an emerging treatment strategy for triple-negative breast cancer (TNBC), immunotherapy acts in part by inducing ferroptosis. Recent studies have shown that protein arginine methyltransferase 5 (PRMT5) has distinct roles in immunotherapy among multiple cancers by modulating the tumor microenvironment. However, the role of PRMT5 during ferroptosis, especially for TNBC immunotherapy, is unclear.PRMT5 expression in TNBC was measured by IHC (immunohistochemistry) staining. To explore the function of PRMT5 in ferroptosis inducers and immunotherapy, functional experiments were conducted. A panel of biochemical assays was used to discover potential mechanisms.PRMT5 promoted ferroptosis resistance in TNBC but impaired ferroptosis resistance in non-TNBC. Mechanistically, PRMT5 selectively methylated KEAP1 and thereby downregulated NRF2 and its downstream targets which can be divided into two groups: pro-ferroptosis and anti-ferroptosis. We found that the cellular ferrous level might be a critical factor in determining cell fate as NRF2 changes. In the context of higher ferrous concentrations in TNBC cells, PRMT5 inhibited the NRF2/HMOX1 pathway and slowed the import of ferrous. In addition, a high PRMT5 protein level indicated strong resistance of TNBC to immunotherapy, and PRMT5 inhibitors potentiated the therapeutic efficacy of immunotherapy.Our results reveal that the activation of PRMT5 can modulate iron metabolism and drive resistance to ferroptosis inducers and immunotherapy. Accordingly, PRMT5 can be used as a target to change the immune resistance of TNBC.
Optical coherence tomography for diagnosing recurrent or residual basal cell carcinoma after topical treatment: A diagnostic cohort study
Authors: Tom Wolswijk, Fieke Adan, Patricia Joan Nelemans, Aniek Defauwes, Klara Mosterd
Journal: Journal of the American Academy of Dermatology (2023)

Recurrent/residual basal cell carcinoma (BCC) after topical treatment may not be visible during clinical and dermatoscopic examination (CDE). Optical coherence tomography (OCT) may detect these subclinical recurrences or residues.To compare the diagnostic accuracy of CDE with that of CDE combined with OCT (CDE-OCT) for detecting recurrent/residual BCC after topical treatment of superficial BCC.In this diagnostic cohort study, the suspicion level for recurrence or residue was recorded on a 5-point confidence scale. All patients with high suspicion of recurrence or residue based on CDE and/or CDE-OCT were referred for punch biopsy. Patients with a low suspicion on CDE and CDE-OCT were asked to (voluntarily) undergo a control biopsy. Histopathologic results of the biopsy were used for verification of CDE and CDE-OCT diagnoses (gold standard).This study included 100 patients. A histopathologic recurrent/residual BCC was found in 20 patients. For recurrence or residue detection, sensitivity was 100% (20 of 20) for CDE-OCT and 60% (12 of 20) for CDE (P = .005) and specificity was 95% for CDE-OCT and 96.3% for CDE (P = .317). The area under the curve for CDE-OCT (0.98) was significantly higher than that for CDE (0.77) (P = .001).Results are based on 2 OCT assessors.Compared with CDE alone, CDE-OCT results in a significantly higher ability to detect recurrent/residual BCCs after topical treatment.
In Situ Precision Cell Electrospinning as an Efficient Stem Cell Delivery Approach for Cutaneous Wound Healing
Authors: Zhengbo Wen, Yuxin Chen, Peilin Liao, Fengyu Wang, Weiping Zeng, Shoupei Liu, Haibing Wu, Ning Wang, Lorenzo Moroni, Minmin Zhang, Yuyou Duan, Honglin Chen
Journal: Advanced Healthcare Materials (2023)

Mesenchymal stem cell (MSC) therapies have been brought forward as a promising treatment modality for cutaneous wound healing. However, current approaches for stem cell delivery have many drawbacks, such as lack of targetability and cell loss, leading to poor efficacy of stem cell therapy. To overcome these problems, in the present study, an in situ cell electrospinning system is developed as an attractive approach for stem cell delivery. MSCs have a high cell viability of over 90% even with a high applied voltage of 15 kV post-cell electrospinning process. In addition, cell electrospinning does not show any negative effect on the surface marker expression and differentiation capacity of MSCs. In vivo studies demonstrate that in situ cell electrospinning treatment can promote cutaneous wound healing through direct deposition of bioactive fish gelatin fibers and MSCs onto wound sites, leading to a synergic therapeutic effect. The approach enhances extracellular matrix remodeling by increasing collagen deposition, promotes angiogenesis by increasing the expression of vascular endothelial growth factor (VEGF) and forming small blood vessels, and dramatically reduces the expression of interleukin-6 (IL-6) during wound healing. The use of in situ cell electrospinning system potentially provides a rapid, no touch, personalized treatment for cutaneous wound healing.
Convergence of Calcium Channel Regulation and Mechanotransduction in Skeletal Regenerative Biomaterial Design
Authors: Jonnby S. LaGuardia, Kaavian Shariati, Meiwand Bedar, Xiaoyan Ren, Shahrzad Moghadam, Kelly X. Huang, Wei Chen, Youngnam Kang, Dean T. Yamaguchi, Justine C. Lee
Journal: Advanced Healthcare Materials (2023)

Cells are known to perceive their microenvironment through extracellular and intracellular mechanical signals. Upon sensing mechanical stimuli, cells can initiate various downstream signaling pathways that are vital to regulating proliferation, growth, and homeostasis. One such physiologic activity modulated by mechanical stimuli is osteogenic differentiation. The process of osteogenic mechanotransduction is regulated by numerous calcium ion channels-including channels coupled to cilia, mechanosensitive and voltage-sensitive channels, and channels associated with the endoplasmic reticulum. Evidence suggests these channels are implicated in osteogenic pathways such as the YAP/TAZ and canonical Wnt pathways. This review aims to describe the involvement of calcium channels in regulating osteogenic differentiation in response to mechanical loading and characterize the fashion in which those channels directly or indirectly mediate this process. The mechanotransduction pathway is a promising target for the development of regenerative materials for clinical applications due to its independence from exogenous growth factor supplementation. As such, also described are examples of osteogenic biomaterial strategies that involve the discussed calcium ion channels, calcium-dependent cellular structures, or calcium ion-regulating cellular features. Understanding the distinct ways calcium channels and signaling regulate these processes may uncover potential targets for advancing biomaterials with regenerative osteogenic capabilities.
Long-acting refillable nanofluidic implant confers protection against SHIV infection in nonhuman primates
Authors: Fernanda P. Pons-Faudoa, Nicola Di Trani, Simone Capuani, Jocelyn Nikita Campa-Carranza, Bharti Nehete, Suman Sharma, Kathryn A. Shelton, Lane R. Bushman, Farah Abdelmawla, Martin Williams, Laura Roon, David Nerguizian, Corrine Ying Xuan Chua, Michael M. Ittmann, Joan E. Nichols, Jason T. Kimata, Peter L. Anderson, Pramod N. Nehete, Roberto C. Arduino, Alessandro Grattoni
Journal: Science Translational Medicine (2023)

The impact of pre-exposure prophylaxis (PrEP) on slowing the global HIV epidemic hinges on effective drugs and delivery platforms. Oral drug regimens are the pillar of HIV PrEP, but variable adherence has spurred development of long-acting delivery systems with the aim of increasing PrEP access, uptake, and persistence. We have developed a long-acting subcutaneous nanofluidic implant that can be refilled transcutaneously for sustained release of the HIV drug islatravir, a nucleoside reverse transcriptase translocation inhibitor that is used for HIV PrEP. In rhesus macaques, the islatravir-eluting implants achieved constant concentrations of islatravir in plasma (median 3.14 nM) and islatravir triphosphate in peripheral blood mononuclear cells (median 0.16 picomole per 106 cells) for more than 20 months. These drug concentrations were above the established PrEP protection threshold. In two unblinded, placebo-controlled studies, islatravir-eluting implants conferred 100% protection against infection with SHIVSF162P3 after repeated low-dose rectal or vaginal challenge in male or female rhesus macaques, respectively, compared to placebo control groups. The islatravir-eluting implants were well tolerated with mild local tissue inflammation and no signs of systemic toxicity over the 20-month study period. This refillable islatravir-eluting implant has potential as a long-acting drug delivery system for HIV PrEP.
Endoscopy E-Videos – recently published
Journal: Endoscopy (2023)

Comment on: Endoscopic vacuum therapy in a patient without nasal accessEndoscopy 2023; 55(S 01): E406-E407DOI: 10.1055/a-1981-1880 Comment on: “Snare-pulley” clip-with-line technique to prevent polyp migration after endoscopic resection of a polyp in the third portion of the duodenumEndoscopy 2023; 55(S 01): E431-E432DOI: 10.1055/a-1997-9429 Comment on: A simple endoscopic full-thickness plication procedure for the treatment of gastroesophageal reflux diseaseEndoscopy 2023; 55(S 01): E444-E445DOI: 10.1055/a-2025-1040 Comment on: Endoscopic coagulation for massive bleeding from a gallbladder ulcer after endoscopic ultrasound-guided gallbladder drainageEndoscopy 2023; 55(S 01): E450-E451DOI: 10.1055/a-2015-2804
Endoscopy International Open – recently published
Journal: Endoscopy (2023)

Comment on: Endoscopic entero-enteral bypass to treat postsurgical benign complications of hepatico-jejunostomy: Update of a 7-year single-center experienceEndosc Int Open 2023; 11(04): E394-E400DOI: 10.1055/a-2032-3077 Comment on: Fatal outcomes of endoscopy: an analysis from the coronerʼs point of viewEndosc Int Open 2023; 11(04): E435-E439DOI: 10.1055/a-2057-4174 Comment on: Investigation of the efficacy of an innovative endoscope drying and storage method in a simulated ERCP settingEndosc Int Open 2023; 11(04): E419-E425DOI: 10.1055/a-2017-3872
Endoscopic ultrasound-guided gastroenterostomy with lumen-apposing metal stents: a retrospective multicentric comparison of wireless and over-the-wire techniques
Authors: Laurent Monino, Enrique Perez-Cuadrado-Robles, Jean-Michel Gonzalez, Christophe Snauwaert, Hadrien Alric, Mohamed Gasmi, Sohaib Ouazzani, Hedi Benosman, Pierre H. Deprez, Gabriel Rahmi, Christophe Cellier, Tom G. Moreels, Marc Barthet
Journal: Endoscopy (2023)

Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) using lumen-apposing metal stents (LAMSs) appears to be effective and safe in gastric outlet obstruction (GOO); however, the EUS-GE procedure is not standardized, with the use of assisted or direct methods still debated. The aim of this study was to compare the outcomes of EUS-GE techniques focusing on an assisted with orointestinal drain wireless endoscopic simplified technique (WEST) and the nonassisted direct technique over a guidewire (DTOG).This was a multicenter European retrospective study involving four tertiary centers. Consecutive patients who underwent EUS-GE for GOO between August 2017 and May 2022 were included. The primary aim was to compare the technical success and adverse event (AE) rates of the different EUS-GE techniques. Clinical success was also analyzed.71 patients (mean [SD] age 66.2 10 years; 42.3 % men; 80.3 % malignant etiology) were included. Technical success was higher in the WEST group (95.1 % vs. 73.3 %; estimate of relative risk from odds ratio (eRR) 3.2, 95 %CI 0.94-10.9; P = 0.01). The rate of AEs was lower in the WEST group (14.6 % vs. 46.7 %; eRR 2.3, 95 %CI 1.2-4.5; P = 0.007). Clinical success was comparable between the two groups at 1 month (97.5 % vs. 89.3 %). The median follow-up was 5 months (range 1-57).The WEST resulted in a higher technical success rate with fewer AEs, with clinical success comparable with the DTOG. Therefore, the WEST (with an orointestinal drain) should be preferred when performing EUS-GE.
Organization of Cancer Specialists in US Physician Practices and Health Systems
Authors: Christina A. Nguyen, Nancy D. Beaulieu, Alexi A. Wright, David M. Cutler, Nancy L. Keating, Mary Beth Landrum
Journal: Journal of Clinical Oncology (2023)

To describe the supply of cancer specialists, the organization of cancer care within versus outside of health systems, and the distance to multispecialty cancer centers.
Notch signaling drives intestinal graft-versus-host disease in mice and nonhuman primates
Authors: Victor Tkachev, Ashley Vanderbeck, Eric Perkey, Scott N. Furlan, Connor McGuckin, Daniela Gómez Atria, Ulrike Gerdemann, Xianliang Rui, Jennifer Lane, Daniel J. Hunt, Hengqi Zheng, Lucrezia Colonna, Michelle Hoffman, Alison Yu, Riley Outen, Samantha Kelly, Anneka Allman, Ute Koch, Freddy Radtke, Burkhard Ludewig, Brandon Burbach, Yoji Shimizu, Angela Panoskaltsis-Mortari, Guoying Chen, Stephen M. Carpenter, Olivier Harari, Frank Kuhnert, Gavin Thurston, Bruce R. Blazar, Leslie S. Kean, Ivan Maillard
Journal: Science Translational Medicine (2023)

Notch signaling promotes T cell pathogenicity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) in mice, with a dominant role for the Delta-like Notch ligand DLL4. To assess whether Notch’s effects are evolutionarily conserved and to identify the mechanisms of Notch signaling inhibition, we studied antibody-mediated DLL4 blockade in a nonhuman primate (NHP) model similar to human allo-HCT. Short-term DLL4 blockade improved posttransplant survival with durable protection from gastrointestinal GVHD in particular. Unlike prior immunosuppressive strategies tested in the NHP GVHD model, anti-DLL4 interfered with a T cell transcriptional program associated with intestinal infiltration. In cross-species investigations, Notch inhibition decreased surface abundance of the gut-homing integrin α4β7 in conventional T cells while preserving α4β7 in regulatory T cells, with findings suggesting increased β1 competition for α4 binding in conventional T cells. Secondary lymphoid organ fibroblastic reticular cells emerged as the critical cellular source of Delta-like Notch ligands for Notch-mediated up-regulation of α4β7 integrin in T cells after allo-HCT. Together, DLL4-Notch blockade decreased effector T cell infiltration into the gut, with increased regulatory to conventional T cell ratios early after allo-HCT. Our results identify a conserved, biologically unique, and targetable role of DLL4-Notch signaling in intestinal GVHD.
Role of Diet–Microbiome Interaction in Gastrointestinal Disorders and Strategies to Modulate Them with Microbiome-Targeted Therapies
Authors: Ajita Jadhav, Aditya Bajaj, Yang Xiao, Manasvini Markandey, Vineet Ahuja, Purna C. Kashyap
Journal: Annual Review of Nutrition (2023)

Diet is an important determinant of health and consequently is often implicated in the development of disease, particularly gastrointestinal (GI) diseases, given the high prevalence of meal-related symptoms. The mechanisms underlying diet-driven pathophysiology are not well understood, but recent studies suggest that gut microbiota may mediate the effect of diet on GI physiology. In this review, we focus primarily on two distinct GI diseases where the role of diet has been best studied: irritable bowel syndrome and inflammatory bowel disease. We discuss how the concurrent and sequential utilization of dietary nutrients by the host and gut microbiota determines the eventual bioactive metabolite profiles in the gut and the biological effect of these metabolites on GI physiology. We highlight several concepts that can be gleaned from these findings, such as how distinct effects of an individual metabolite can influence diverse GI diseases, the effect of similar dietary interventions on multiple disease states, and the need for extensive phenotyping and data collection to help make personalized diet recommendations.
Targeting CCR7-PI3Kγ overcomes resistance to tyrosine kinase inhibitors in ALK-rearranged lymphoma
Authors: Cristina Mastini, Marco Campisi, Enrico Patrucco, Giulia Mura, Antonio Ferreira, Carlotta Costa, Chiara Ambrogio, Giulia Germena, Cinzia Martinengo, Silvia Peola, Ines Mota, Elena Vissio, Luca Molinaro, Maddalena Arigoni, Martina Olivero, Raffaele Calogero, Nina Prokoph, Fabrizio Tabbò, Brent Shoji, Laurence Brugieres, Birgit Geoerger, Suzanne D. Turner, Carlos Cuesta-Mateos, Deborah D’Aliberti, Luca Mologni, Rocco Piazza, Carlo Gambacorti-Passerini, Giorgio G. Inghirami, Valeria Chiono, Roger D. Kamm, Emilio Hirsch, Raphael Koch, David M. Weinstock, Jon C. Aster, Claudia Voena, Roberto Chiarle
Journal: Science Translational Medicine (2023)

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show potent efficacy in several ALK-driven tumors, but the development of resistance limits their long-term clinical impact. Although resistance mechanisms have been studied extensively in ALK-driven non–small cell lung cancer, they are poorly understood in ALK-driven anaplastic large cell lymphoma (ALCL). Here, we identify a survival pathway supported by the tumor microenvironment that activates phosphatidylinositol 3-kinase γ (PI3K-γ) signaling through the C-C motif chemokine receptor 7 (CCR7). We found increased PI3K signaling in patients and ALCL cell lines resistant to ALK TKIs. PI3Kγ expression was predictive of a lack of response to ALK TKI in patients with ALCL. Expression of CCR7, PI3Kγ, and PI3Kδ were up-regulated during ALK or STAT3 inhibition or degradation and a constitutively active PI3Kγ isoform cooperated with oncogenic ALK to accelerate lymphomagenesis in mice. In a three-dimensional microfluidic chip, endothelial cells that produce the CCR7 ligands CCL19/CCL21 protected ALCL cells from apoptosis induced by crizotinib. The PI3Kγ/δ inhibitor duvelisib potentiated crizotinib activity against ALCL lines and patient-derived xenografts. Furthermore, genetic deletion of CCR7 blocked the central nervous system dissemination and perivascular growth of ALCL in mice treated with crizotinib. Thus, blockade of PI3Kγ or CCR7 signaling together with ALK TKI treatment reduces primary resistance and the survival of persister lymphoma cells in ALCL.
Gilteritinib in Combination With Induction and Consolidation Chemotherapy and as Maintenance Therapy: A Phase IB Study in Patients With Newly Diagnosed AML
Authors: Keith W. Pratz, Mohamad Cherry, Jessica K. Altman, Brenda W. Cooper, Nikolai A. Podoltsev, Jose Carlos Cruz, Tara L. Lin, Gary J. Schiller, Joseph G. Jurcic, Adam Asch, Ruishan Wu, Jason E. Hill, Stanley C. Gill, Angela J. James, Elizabeth Shima Rich, Nahla Hasabou, Alexander E. Perl, Mark J. Levis
Journal: Journal of Clinical Oncology (2023)

Gilteritinib is a type 1 FLT3 inhibitor active as monotherapy for relapsed or refractory FLT3-mutated AML. We investigated the safety, tolerability, and efficacy of gilteritinib incorporated into intensive induction and consolidation chemotherapy, and as maintenance therapy for adult patients with newly diagnosed, non-favorable-risk AML.In this phase IB study (2215-CL-0103; ClinicalTrials.gov identifier: NCT02236013), 103 participants were screened and 80 were allocated to treatment. The study was divided into four parts: dose escalation, dose expansion, investigation of alternate anthracycline and gilteritinib schedule, and continuous gilteritinib during consolidation.After dose escalation, 120 mg gilteritinib once daily was chosen for further study. There were 58 participants evaluable for response at this dose, 36 of whom harbored FLT3 mutations. For participants with FLT3-mutated AML, the composite complete response (CRc) rate was 89% (83% were conventional complete responses), all achieved after a single induction cycle. The median overall survival time was 46.1 months. Gilteritinib was well-tolerated in this context although the median time to count recovery during induction was approximately 40 days. Longer time-to-count recovery was associated with higher trough levels of gilteritinib, which, in turn, were associated with azole use. The recommended regimen is gilteritinib at a dose of 120 mg once daily from days 4 to 17 or 8 to 21 of a 7 + 3 induction with either idarubicin or daunorubicin and from day 1 continuously with high-dose cytarabine consolidation. Maintenance therapy with gilteritinib was well-tolerated.These results demonstrated the safety and tolerability of gilteritinib incorporated into an induction and consolidation chemotherapy regimen, and as single-agent maintenance therapy for patients with newly diagnosed FLT3-mutant AML. The data herein provide an important framework for the design of randomized trials comparing gilteritinib with other FLT3 inhibitors.
Tai Ji Quan and Fall Risk
Authors: Ya-Ting Hu, Szu-Yuan Wu, Yung-Shuo Kao
Journal: Journal of Clinical Oncology (2023)

We are glad to read the study by Winters-Stone et al, 1 which showed that there was no substantial decrease in falls observed for Tai Ji Quan or strength training compared with the stretching control group in postmenopausal female patients who had undergone chemotherapy.However, there are several concerns that need to be addressed and discussed in this study to enhance its validity and reliability.